Yersinia pestis, the causative agent of plague is constitutively serum resistant; however, the mechanism by which this bacterium avoids destruction via complement-mediated lysis is not understood. The Y. pestis KIM and C092 genomes both encode four Ail family members. Ail family proteins play a critical role in bacteria-host cell interaction and in the resistance to complement-mediated killing in other bacterial pathogens, including Y. enterocolitica. Preliminary studies demonstrated that the Y. pestis ailC gene product is essential for survival in normal human serum, but not in heat-inactivated serum. Additional studies revealed that the AilC protein was essential for the efficient type III secretion system (T3SS)-mediated injection of Yops into epithelial (HeLa) cells, suggesting that AilC plays a critical role in host cell attachment or delivery of T3S effector proteins. This project will further characterize the role of the Y. pestis AilC protein in the pathogenesis of plague. The goals of this project are (i) to determine the role of AilC in the resistance of Y. pestis to complement-mediated killing and (ii) to determine the role of AilC in bacterial adhesion, invasion, Yop injection and bacterial virulence. Y. pestis grows, multiplies and is even transmitted in blood; therefore, this pathogen must avoid destruction via complement-mediated lysis and/or bacterial phagocytosis. Preliminary data suggests that the AilC protein is surface-exposed, highly expressed protein that plays an important role in both of these processes. The proposed studies will further characterize the role of AilC in the pathogenesis of plague and validate AilC as a potential vaccine candidate and/or a target for small molecules or immunotherapies. To produce disease in humans the bacterium Yersinia pestis must be able to survive in human blood. We have identified a Y. pestis protein called AilC that is essential to thwart blood defense systems that normally kill bacteria. Studies presented in this proposal will determine how the AilC protein protects the bacterium, a process that could be a target for new anti-bacterial drugs. [unreadable] [unreadable] [unreadable] [unreadable]